Central tolerance
Central tolerance is the mechanism by which newly developing T cells and B cells are rendered non-reactive to self.[1] Central tolerance is distinct from periphery tolerance in that it occurs while cells are still present in the primary lymphoid organs (thymus and bone-marrow), prior to export into the periphery, while peripheral tolerance is generated after the cells reach the periphery. Regulatory T cells can be considered both central tolerance and peripheral tolerance mechanisms, as they can be generated from self-reactive T cells in the thymus during T cell differentiation, but they exert their immune suppression in the periphery on other self-reactive T cells.
Requirement for central tolerance
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Central tolerance is induced in the thymus, where developing thymocytes that recognize self-peptide–MHC complexes with too high affinity are deleted(the T cell receptor) and B cells (the B cell receptor, also known as antibody). The T cell receptor and B cell receptor genes contain multiple gene fragments which need to be physically recombined together to make a functional gene, with billions of alternative possibilities for the order of rearrangement and the deliberate introduction of mutation during the rearrangement. This random Generation of Diversity allows the creation of T cell receptors and antibodies against antigens which the host has never encountered during its evolutionary history, and is thus a powerful defense against rapidly evolving pathogens. Conversely, the random nature of the Generation of Diversity creates, by chance, a population of T cells and B cells that are self-reactive (ie, recognize an antigen which is a constituent component of the host).
In mammals the process occurs in the thymus (T cells)[2][3] and bone marrow (B cells). These are the two primary lymphoid organs where T cells and B cells mature. During the maturation phases of both T cells and B cells the cells are sensitive to antigen-recognition. Unlike mature peripheral lymphocytes, which become activated upon encountering their specific antigen, the immature lymphocytes respond to stimulation with antigen by undergoing a rewiring of the cellular processes. The response to antigen at this stage depends on the properties of the antigen, the cell type and the developmental stage, and can lead to the cell becoming non-responsive (anergic), undergoing directed suicide (negative selection), altering its antigen receptor (receptor editing) or entering a regulatory lineage.
As this tolerance is dependent on encountering the self-antigens during maturation, lymphocytes can only develop central tolerance towards those antigens present in primary lymphoid organs. In the case of B cells in the bone marrow, this is limited to ubiquitous and bone-marrow specific antigens present in the bone-marrow and additional antigens imported by circulation (either as raw antigens or presented by circulating dendritic cells). The thymus has an additional source of antigen through the action of the transcription factor AIRE, which allows the expression of organ-specific antigens such as insulin in the thymus.
Mechanisms of central tolerance
B cell tolerance
The recognition of antigens by the immature B cells in the bone marrow is critical to the development of immunological tolerance to self. This process produces a population of B cells that do not recognize self-antigens but may recognize antigens derived from pathogens (non-self).
Immature B cells expressing only surface IgM molecules undergo negative selection by recognizing self-molecules present in the bone marrow. This antigen induced loss of cells from the B cell repertoire is known as clonal deletion. B cells may encounter two types of antigen, multivalent cell surface antigens or low valence soluble antigens:
- When immature B cells express surface IgM that recognizes ubiquitous self-cell-surface (i.e. multivalent) antigens (such as those of the MHC) they are eliminated by a process known as clonal deletion. These B cells are believed to undergo programmed cell death or apoptosis. However, there is an interval before apoptosis during which the self-reactive B cell may be rescued by further gene rearrangements (receptor editing) that may replace the self-reactive receptor with a new receptor, which is not auto-reactive [4].
- Immature B cells that bind soluble self-antigens (i.e. low valence) do not die but their ability to express IgM on their surfaces is lost. Thus, they migrate to the periphery only expressing IgD and are unable to respond to antigen. These B cells are said to be anergic. Only B cells that do not encounter antigen whilst they are maturing in the bone marrow can be activated after they enter the periphery. These cells bear both IgM and IgD receptors and constitute the repertoire of B cells that recognize foreign antigen.[5]
Even if mature self-reacting B cells were to survive intact, they would very rarely be activated. This is because B cells need co-stimulatory signals from T cells as well as the presence of its recognized antigen to proliferate and produce antibodies (Peripheral tolerance). If mature peripheral B cells encounter multivalent antigen (eg cell surfaces) they are eliminated via apoptosis. If mature B cells recognize soluble antigen in the periphery in the absence of T cell help, they lose surface IgM receptors and become anergic.[6]
T cell tolerance
T cells are selected for survival much more rigorously than B cells. They undergo both positive and negative selection to produce T cells that recognize self- major histocompatibility complex (MHC) molecules but do not recognize self-peptides. T cell tolerance is induced in the thymus
Positive selection occurs in the thymic cortex. This process is normally mediated exclusively by thymic epithelial cells, which are rich in surface MHC molecules. If a maturing T cell is able to bind to a surface MHC molecule in the thymus it is saved from programmed cell death; those cells failing to recognize MHC on thymic epithelial cells die. Thus, positive selection ensures that T cells only recognize antigen in association with MHC. This is important because one of the primary functions of T cells is to identify and respond to infected host cells as opposed to extracellular pathogens. The process of positive selection also determines whether a T cell ultimately becomes a CD4+ cell or a CD8+ cell: prior to positive selection, all thymocytes are double positive (CD4+CD8+) i.e. bear both co-receptors. During positive selection they are transformed into either CD4+CD8- or CD8+CD4- T cells depending on whether they recognize MHC II or MHC I, respectively. [5]
After positive selection, T cells undergo negative selection in a process analogous to the induction of self-tolerance in B cells, this occurs mainly in the cortico-medullary junction and is mediated predominately by medulary thymic epithelial cells (mTECS) and dendritic cells. These cells display "self" antigens to developing T-cells and signal those "self-reactive" T-cells to die via programed cell death (apoptosis) and thereby deleted from the T cell repertoire. This process is highly dependent on the ectopic expression of tissue specific antigens (TSAs) which is regulated by AIRE (the Autoimmune Regulator).[6]
This clonal deletion of T cells in the thymus cannot eliminate every potentially self-reactive T cell; T cells that recognize proteins only found at other sites in the body or only at certain times of development (eg after puberty) must be inactivated in the periphery.
Regulatory T cells are another group of T cells maturing in the thymus, they are also involved with immune regulation but are not directly involved in central tolerance.[6]
Genetic diseases caused by defects in central tolerance
Genetic defects in central tolerance can lead to autoimmunity.
- Autoimmune Polyendocrinopathy Syndrome Type I is caused by mutations in the human gene AIRE. This leads to a lack of expression of peripheral antigens in the thymus, and hence a lack of negative selection towards key peripheral proteins such as insulin. [7][8] Multiple autoimmune symptoms result.
- Immunodysregulation polyendocrinopathy enteropathy X-linked syndrome is caused by mutations in the human gene Foxp3. [9] In the absence of Foxp3, auto reactive T cells are unable to become regulatory T cells, and therefore instead of inhibiting disease in the periphery they aid disease progression. [10][11][12] As Foxp3 is on the X-chromosome and the disease is fatal early on in life, only males can develop IPEX.
See also
References
- ^ Lecture 12. Tolerance
- ^ Sprent J, Kishimoto H (2001). "The thymus and central tolerance". Philos Trans R Soc Lond B Biol Sci. 356 (1409): 609–16. doi:10.1098/rstb.2001.0846. PMC 1088448. PMID 11375064.
- ^ Hogquist K, Baldwin T, Jameson S (2005). "Central tolerance: learning self-control in the thymus". Nat Rev Immunol. 5 (10): 772–82. doi:10.1038/nri1707. PMID 16200080.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Halverson R, Torres R, Pelanda R (2004). "Receptor editing is the main mechanism of B cell tolerance toward membrane antigens". Nat Immunol. 5 (6): 645–50. doi:10.1038/ni1076. PMID 15156139.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ a b Charles A. Janeway, Paul Travers, Mark Walport, Mark Shlomchik (2001), Immunobiology: The Immune System In Health And Disease 5th Ed, Garland Publishing
{{citation}}: CS1 maint: multiple names: authors list (link) - ^ a b c Thomas J. Kindt, Barbara A. Osborne, Richard A. Goldsby (2006), Kuby Immunology 6th Ed, W. H. Freeman
{{citation}}: CS1 maint: multiple names: authors list (link) - ^ Anderson, M.S. et al. (2002) Projection of an Immunological Self-Shadow Within the Thymus by the Aire Protein. Science 298 (5597), 1395-1401
- ^ Liston, A. et al. (2003) Aire regulates negative selection of organ-specific T cells. Nat Immunol 4 (4), 350-354
- ^ Bennett C, Christie J, Ramsdell F, Brunkow M, Ferguson P, Whitesell L, Kelly T, Saulsbury F, Chance P, Ochs H (2001). "The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3". Nat Genet. 27 (1): 20–1. doi:10.1038/83713. PMID 11137993.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Hori S, Nomura T, Sakaguchi S (2003). "Control of regulatory T cell development by the transcription factor Foxp3". Science. 299 (5609): 1057–61. doi:10.1126/science.1079490. PMID 12522256.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Fontenot JD, Gavin MA, Rudensky AY (2003). "Foxp3 programs the development and function of CD4+CD25+ regulatory T cells". Nature Immunology. 4 (4): 330–6. doi:10.1038/ni904. PMID 12612578.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY (2005). "Regulatory T cell lineage specification by the forkhead transcription factor Foxp3". Immunity. 22 (3): 329–41. doi:10.1016/j.immuni.2005.01.016. PMID 15780990.
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